FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

Ursic-Bedoya, J.; Desandre, G.; Chavey, C.; Marie, P.; Polizzi, A.; Riviere, B.; Guillou, H.; Assenat, E.; Hibner, U.; Gregoire, D.

doi:10.1101/2023.09.15.557921

bioRxiv · 10.1101/2023.09.15.557921

FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

Ursic-Bedoya, J.·Desandre, G.·Chavey, C.·Marie, P.·Polizzi, A.·Riviere, B.·Guillou, H.·Assenat, E.·Hibner, U.·Gregoire, D.

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Abstract

FGF19 hormone has pleiotropic metabolic functions, notably the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormones metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormones oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.

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Ursic-Bedoya, J., Desandre, G., Chavey, C., Marie, P., Polizzi, A., Riviere, B., Guillou, H., Assenat, E., Hibner, U., Gregoire, D.. 2023-09-17. FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis. https://doi.org/10.1101/2023.09.15.557921

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